The overall objective of this research proposal is to determine the mechanisms that underlie motor complications ("peak-dose" dyskinesia and "end of dose" failure) in MPTP parkinsonian monkeys treated with levodopa (L-dopa). The progressive loss of dopaminergic neurons in the pars compacta of the substantia nigra is the critical lesion in Parkinson's disease and reduces dopaminergic terminals in the striatum. Motor function in parkinsonian patients is critically dependent on sustained striatal dopaminergic stimulation. L-dopa replishment therapy has been the major advance in the treatment of Parkinson's disease. The hypothesis that is the foundation of this proposal is that as the disease progresses there is a decrease in the striatal storage capacity for dopamine. This results in high peak brain extracellular fluid levels of L-dopa, which is disproportionately metabolized to 3-0-methyldopa instead of dopamine. High peak striatal extracellular fluid accumulation of 3-0-methyldopa would then interfer with the normal delivery of dopamine to its postsynaptic receptor or interfere with its function. Thirty male cynomolgous monkeys will be used in this study. Twenty two monkeys will be made parkinsonian by intravenous injections of MPTP. Eight animals will be used as controls. The control group will consist of four animals that will receive chronic L-dopa treatment and four animals that will not. In the parkinsonian group 18 animals will receive chronic L-dopa treatment and four animals will not. Chronic L-dopa treatment of parkinsonian monkeys will start 90 days after the final MPTP dose. L-dopa will be administered orally twice daily for 12 weeks. Parkinson's disease is the best understood of the neurodgenerative disorders for which a partially effective neurotransmitter replenishment therapy has been devised. A better understanding of how L-dopa replenishment therapy works, and what the mechanisms of L-dopa therapy complications are would be invaluable in designing neurotransmitter replenishment therapies for neurodegenerative diseases in general.